Mechanical thrombectomy combined with intravenous thrombolysis for acute ischemic stroke: a systematic review and meta-analyses

To assess the clinical value of mechanical thrombectomy (MT) combined with intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) by comparing it with the MT alone. In this study, we conducted a comprehensive meta-analysis of both observational and randomized controlled studies (RCTs) to investigate various outcomes. Our search for relevant studies was conducted between January 2011 and June 2022 in four major databases: PubMed, Embase, WOS, and Cochrane Library. We collected data on several outcomes, including functional independence (FI; defined as modified Rankin Scale score of 0 to 2), excellent outcomes (mRS 0–1), successful recanalization (SR), symptomatic intracerebral hemorrhage (sICH), any intracerebral hemorrhage (aICH), and mortality at three months or discharge. The primary efficacy outcome and safety outcome were FI and sICH, respectively, whereas excellent outcomes and SR were considered secondary efficacy outcomes. Additionally, mortality and aICH were analyzed as secondary safety outcomes. We employed the Mantel–Haenszel fixed-effects model for RCTs when I2 < 50%, otherwise the random-effects model was utilized. For observational studies and subgroup analyses, we used the random-effects model to minimize potential bias. A total of 55 eligible studies (nine RCTs and 46 observational studies) were included. For RCTs, the MT + IVT group was superior in FI (OR: 1.27, 95% CI: 1.11–1.46), excellent outcomes (OR: 1.21, 95% CI: 1.03–1.43), SR (OR: 1.23, 95% CI: 1.05–1.45), mortality (OR: 0.72, 95% CI: 0.54–0.97) in crude analyses. In adjusted analyses, the MT + IVT group reduced the risk of mortality (OR: 0.65, 95% CI: 0.49–0.88). However, the difference in FI between the MT + IVT group and the MT alone group was not significant (OR: 1.17, 95% CI: 0.99–1.38, Fig. 3a). For observational studies, the results of FI (OR: 1.34, 95% CI: 1.16–1.33), excellent outcomes (OR: 1.30, 95% CI: 1.09–1.54), SR (OR: 1.23, 95% CI: 1.05–1.44), mortality (OR: 0.70, 95% CI: 0.64–0.77) in the MT + IVT group were better. Additionally, the MT + IVT group increased the risk of hemorrhagic transformation (HT) including sICH (OR: 1.16, 95% CI: 1.11–1.21) and aICH (OR: 1.24, 95% CI: 1.05–1.46) in crude analyses. In adjusted analyses, significant better outcomes were seen in the MT + IVT group on FI (OR: 1.36, 95% CI: 1.21–1.52), excellent outcomes (OR: 1.49, 95% CI: 1.26–1.75), and mortality (OR: 0.73, 95% CI: 0.56–0.94). The MT + IVT therapy did improve the prognosis for AIS patients and did not increase the risk of HT compared with MT alone therapy.


Participants and interventions.
We included AIS patients with LVO in the anterior circulation. Each participant received the MT alone or IVT + MT therapy. Most of included studies primarily used the medication alteplase. It should be highlighted that we did not exclude some other IVT medications from our analysis even though they were not recommended by the guidelines.
Outcomes. In this study, FI for three months or hospital discharge, defined as a modified Rankin Scale (mRS) score (range,0 to 2), was selected as the primary efficacy outcome. The primary safety indicator was symptomatic intracerebral hemorrhage (sICH) at 24 or 36 h according to Heidelberg Bleeding Classification (HBC) 16 , or European Cooperative Acute Stroke Study 3 classification (ECASS III) 17 , or ECASS II, or Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria 18 .
Quality assessment. Given that we had both RCTs, and observational studies included, we employed the Cochrane Risk of Bias tool (RoB) to assess RCTs, which included blinding, baseline comparison, allocation concealment, and randomization analysis. The modified Newcastle-Ottawa Scales (NOS) were used to assess the authenticity and quality of observational studies 20 . The NOS consisted of three sections: patient selection, study group comparability, and outcome assessment. The methodological quality of studies was assessed using a star system. The NOS can award up to nine points, with NOS ≥ 7 indicating high-quality study. Beyond this, the study was considered "low quality". Sensitivity and publication bias analyses. We performed sensitivity analyses to test the stability of our results by excluding each study one by one. Moreover, contour-enhanced funnel plots, Peter's test and Egger's test were conducted only when at least 10 studies were available to detect publication bias.
Data extraction. Two investigators reviewed each title, abstract, and full-text articles individually to select eligible studies. Any controversies were addressed in discussions with the third author. A Microsoft Excel file had the extracted data that was present. Study title, authors, publication date, study setting, study design, study period, participants, FI, SR, sICH, and mortality definitions, other important outcomes, and adjustment methods were among the extracted study characteristics. Crude data and effects estimate with their 95% CI of crude and adjusted were also included. For more details or unpublished data from conference abstracts, the corresponding authors would be contacted. www.nature.com/scientificreports/ Data synthesis and statistical analysis. Considering the heterogenicity of the methodology, data source, and so on existed in the included studies. We evaluated the inter-study heterogeneity using I 2 tests and the P-value. I 2 values < 25%, 25-50%, 50-75%, 75-100% indicated no, moderate, large, and high levels of heterogeneity, respectively. P-value < 0.1 was considerately statistically significant. For RCTs, the Mantel-Haenszel fixed-effects model was used if I 2 < 50%. Otherwise, the random-effects model was applied. For observational studies and subgroups analysis, wo chose the random-effects model to control the potential bias. After thoroughly reviewing each included study, we analyzed crude data and adjusted data separately to increase the credibility. These methods were applicable to both crude data analysis and adjusted analysis. For studies that used covariates, we included data that was adjusted for covariates by the original authors in the adjusted analysis. Also, we performed subgroup analysis by study design (prospective study and retrospective study), and study area (Asia, European, and America). All the analyses were conducted in the RevMan software version 5.3 and computer program R software version 4.1.1. Unless otherwise noted, all P-values were two-tailed and less than 0.05 was considered statistically significant.
Ethical approval. This article belonged to the category of systematic review and meta-analysis, and we have confirmed that no ethical approval is required.

Results
Literature retrieval and study characteristics. The study process as shown in Fig. 1. There were 4,930 items in total (1,830 from PubMed, 1,428 from WOS, 501 from Embase, and 1,171 from Cochrane Library). 2,863 items were included in the abstract screening after eliminating duplicates. Then 2,774 unrelated studies were excluded. Among the 2774 studies, 1184 were basic experimental studies involving animals and cells, 1023 were reviews, and 567 were studies that did not match the research topic. A total of 88 full-text articles were assessed for eligibility. We excluded 33 studies, 22 of which used therapies other than MT or IVT, seven studies were reviews, and four pieces involved RCTs protocol. Finally, 55 studies 6-9,21-70 met our protocol and were qualitatively synthesized and meta-analyzed. Table 1 displays the characteristics of eligible studies, including the authors and years of publication, study design type, study period, study participants, age, gender, NIHSS score, location of occlusion, FI definition, SR definition, sICH definition, mortality definition, other outcomes, adjustment method, and adjustment of confounding factors. The study evaluated data from 17 nations, including 10 from Europe, four from Asia, two from The North American, and the one from Australia. Nine RCTs and 46 observational studies-29 retrospective (RS), 16 prospective (PS), and one cross-sectional (CS) were included in the analysis. almost all studies used an mRS score ≤ 2 to define FI. Methods to define SR included TICI 2b/3, mTICI 2b/3, and eTICI 2b/3. Additionally, several methods were adopted to assess sICH (ECASS II/III, HBC, and SITS-MOST). A portion of included studies adopted multivariate analysis, multivariate binary logistic regression, and propensity score method (PSM) to adjust the data.
Quality assessment for included studies. According to RoB, most trials were of high quality and possessed a low overall risk of bias. Supplemental Fig. 11 showed the specific details. Due to randomization and blinding items, a trial had a high risk of bias 27 . Additionally, Supplemental Table 4 showed how detailed information from OS were evaluated using the NOS scale. Except for one study 62 , which scored only 6 because controls for comparability between the two groups were omitted from the study. All other studies were rated as "high quality". Crude analysis. Primary outcomes. The results would be reported separately by RCTs and observational studies. Regarding efficacy outcomes, data from the nine RCTs indicated that MT + IVT group had superior FI than the MT alone group (OR: 1.27, 95% CI: 1.11-1.46, Fig. 2a), with large heterogeneity (I 2 = 53%, P = 0.03). About safety outcomes, the results of sICH showed no significant difference between the two groups (OR: 1.13, 95% CI: 0.86-1.49, Fig. 2b), indicating no heterogeneity (I 2 = 0, P = 0.82). Overall, 40 observational studies reported the results for FI, suggesting better results were seen in the MT + IVT group (OR: 1.34, 95% CI: 1.16-1.33, Fig. 2c), with large heterogeneity (I 2 = 70%, P < 0.01). Data on sICH was extracted from 36 observational studies and found a 16% higher risk of HT (OR: 1.16, 95% CI: 1.11-1.21, Fig. 2d) in the MT + IVT group, with no heterogeneity (I 2 = 0, P = 0.80).
About observational studies, better results were seen in the MT + IVT group about the outcomes of excellent outcomes (OR: 1. Subgroup analysis. Due to the limited number of included RCTs, advanced subgroup analysis was performed solely in observational studies. Among the subgroup of study area, there were no distinguishable differences in the outcomes of FI (P = 0.25), excellent outcomes (P = 0.20), sICH (P = 0.31), and mortality (P = 0.53), except for SR (P = 0.04). Specifically, there was non-significance in Asia between two groups (OR: 0.59, 95% CI: 0.29-1.21). However, in contrast to the MT alone therapy, the MT + IVT therapy raised the rate of SR by 51% in Europe (OR: 1.51, 95% CI: 1.23-1.86). All details were depicted in Supplemental Table 1.
Sensitivity analysis. The sensitivity analysis of RCTs in crude data showed the effects of sICH (Supplemental Fig. 5b), SR (Supplemental Fig. 5d), and mortality (Supplemental Fig. 5f) were not substantially modified by exclusion of a certain study. The effect size of FI varied (OR: 1.15, 95% CI: 0.97-1.35, Supplemental Fig. 5a) when one study was excluded 22 . When the trial was eliminated 9 , the total effect sizes showed no discernible improvement (OR: 1.18, 95% CI: 0.99-1.40) in the excellent outcome of MT + IVT therapy. When this study was excluded 22 , a similar outcome (OR: 1.07, 95% CI: 0.89-1.28) was observed. And the MT + IVT group did not increase the risk of aICH (Supplemental Fig. 5d) while removing the study 26 and the trial 25 , the effect sizes were (OR: 1.16, 95% CI: 0.95-1.41) and (OR: 1.18, 95% CI: 0.98-1.44,), respectively. Similar outcomes were seen in the outcome of excellent outcomes (Supplemental Fig. 5c). As followed by the sensitivity analysis of RCTs in adjusted data, the direction of effect size did not change in the outcomes of our interest (Supplemental Fig. 6b-f) except for the FI. The MT + IVT therapy significantly increased FI (OR: 1.23, 95% CI: 1.03-1.48, Supplemental  Fig. 6a) after eliminating the study 23 .
As with the above analyses with observational studies, no significant differences were found in the outcomes of observational studies about crude data (Supplemental Fig. 7a, c-f), with the exception of the sICH (Supplemental Fig. 7b). When excluding the study 71 , the effect of direction changed (OR: 1.11, 95% CI: 0.96-1.29). Referring to observational studies of adjusted data, there were no discernible variations in the outcomes (Supplemental Fig. 8a-f).
The inspection of contour-enhanced funnel plots for observational studies with adjusted data revealed indications of asymmetries in outcomes of FI and sICH (Fig. 5a-b). There was no asymmetry in the mortality results (Supplemental Fig. 10). Additionally, except for sICH (P = 0.01), there was no indication of funnel plot asymmetry in the appropriate Egger's statistical tests for the outcomes of FI (P = 0.46) or mortality (P = 0.67). We did not run the funnel plot, Peter's, or Egger's statistical tests due to the numerous limitations of including RCTs and other observational studies.

Discussion
In this systematic review and meta-analysis, a total of approximately 20,000 patients were included in the final analysis. Overall, MT + IVT treatment significantly improved FI, excellent outcomes, and mortality risk in the observational studies, both in raw and adjusted data. Furthermore, it is crucial to note that although in crude  www.nature.com/scientificreports/ analysis we observed an increased risk of sICH and aICH with MT + IVT treatment, no significant difference was found in the adjusted analysis. In the RCTs, we found that MT + IVT treatment reduced the risk of mortality but did not increase the risk of sICH in either the crude or adjusted analyses. Similar effect size directions emerged in the raw and adjusted data in the FI, excellent outcome, and SR domains, implying that there was no significant difference between the two therapies. In addition, although MT + IVT treatment significantly increased the risk of aICH in the raw data, it was not present in the adjusted data. Clearly, the adjusted analysis was more plausible due to the controlled covariates. The use of IVT prior to MT was previously thought to enhance the likelihood of HT 58,72 . However, our results provided further evidence that MT + IVT treatment did not significantly increase the risk of HT. Particularly, adjusted data from observational studies and RCTs, were used to draw conclusions. www.nature.com/scientificreports/ Of particular note, although we conducted subgroup analyses by study design and area only, these analyses were based on extracting available data directly from the included studies with the aim of minimizing randomization and sampling error. The primary efficacy results derived from the analysis of observational studies in our study were consistent with previous studies 74 . Regarding the outcomes of the FI and sICH between two regimens by evaluating the raw data, non-significances were both seen when comparing the findings of synthesizing RCTs with the meta-analysis carried out by Vidale and colleagues 14 . Notably, our analysis of the adjusted data revealed that the MT + IVT therapy considerably outperformed the MT alone therapy in terms of excellent outcomes, SR, and mortality. Several strengths of this study should be noted, and the following were some of the benefits of this study. First, the breadth of the chosen research-observational studies and RCTs with sizable sample sizes-allowed us to perform joint and subgroup analyses and improve statistical analysis. Second, we conducted crude and adjusted data analyses, which increased the credibility of the findings by accounting for confounding factors. Third, except for the outcomes of FI, we also assessed the excellent outcomes (mRS score: 0-1).
However, some limitations must be remarked upon. First, we routinely followed current clinical guidelines so that we only included AIS patients with occlusion of anterior circulation. But there was a need to know whether the MT therapy would be effective for posterior circulation occlusion. However, few studies were seen in this field after searching for literature. Second, because most of the included studies did not provide adjusted data, we www.nature.com/scientificreports/ performed adjusted analysis by synthesizing only a portion of the included studies, suggesting that the adjusted data were insufficient. Moreover, the number of covariates varied across studies. Third, we only conducted subgroup analyses of study design and area in order to minimize the bias. This may make it challenging for us to investigate additional potential confounders.

Conclusion
In summary, our findings showed that the MT + IVT therapy did, in fact, raise the rate of SR and lower the risk of mortality. Furthermore, we demonstrated that the MT + IVT therapy did not increase the risk of HT compared with the MT alone therapy. Based on the findings of observational studies, we thought that the MT + IVT therapy was more beneficial in achieving the object of FI. Although the results of FI in RCTs showed the same trend, they formally failed to achieve statistical significance. This would obviously call for further RCTs and analysis, both of which are necessary for future work.

Data availability
All data generated or analyzed during this study are included in this published article and its supplementary information files.